Leveraging Glutamatergic Antidepressants for the Treatment of MDD

How is the current understanding of the glutamatergic system’s role in depression shaping treatment options for major depressive disorder (MDD) and treatment-resistant depression (TRD)? 

In this video, Psych Congress Elevate Co-Chairs Craig Chepke, MD, DFAPA, and Kristian Dambrino, DNP, PMHNP-BC, dive into the evolving landscape of glutamatergic antidepressants. The clinicians explore the differences between traditional monoamine and glutamate-based options and unpack the clinical findings regarding glutamatergic antidepressants for TRD treatment. With promise of faster symptom resolution, Chepke and Dambrino highlight how these newer agents can bring hope to discouraged patients who are seeking relief. 

For more news and expert insights on depression, visit Depression Care360. 

Read the Transcript

Craig Chepke, MD, DFAPA: Hi, I'm Craig Chepke. I'm the medical director of Excel Psychiatric Associates in Huntersville, North Carolina, and adjunct associate professor of psychiatry for Atrium Health, and also the scientific director of Psych Congress.

Kristian Dambrino, DNP, PMHNP-BC: I'm Kristian Dambrino. I'm a psychiatric nurse practitioner living and working in Nashville, Tennessee, and the owner of Dambrino Consulting and Wellness, LLC.

Psych Congress Network: How has the understanding of the glutamatergic system's role in MDD evolved, and what distinguishes glutamatergic antidepressants from traditional monoaminergic therapies?

Chepke: When it comes to anything in the brain, we've known for a long time that glutamate plays a big role. It's the most excitatory neurotransmitter, it's the most potent neurotransmitter, and in this cerebral cortex it makes up the majority of the synapses. But in psychiatry, we've not been able to tap into that therapeutically up until pretty recently. 

Now other fields like neurology with epilepsy, they've been working with glutamate for ages, but we're new to this. Really, we finally got our big break a couple decades ago with ketamine. When ketamine was found at subanesthetic doses to have an improvement in depression, we finally had an agent that worked, because it wasn't for lack of trying. There had been a lot of different glutamatergic therapies tried for many psychiatric conditions, including major depressive disorder, but we couldn't get anything to work right.

Then, following on from ketamine, we had esketamine approved for treatment-resistant depression, as well as major depression with suicidal ideation, and most recently, the first oral antidepressant with a glutamatergic mechanism, the combination of dextromethorphan and bupropion. 

Dambrino: Right. We used to think about the theory that supports major depressive disorder, the underpinning of that, being the monoamine hypothesis. Medications really address that, increasing the reuptake or serotonin reuptake inhibitors or norepinephrine reuptake inhibitors. Now we're moving away from that. Even when we think about the glutamatergic synapse, it's a tripartite synapse. There's a major role of astroglia in that. We used to think of astroglia as connective tissue. Now we know that it's more of a system. 

Craig and I have actually talked about this, I compare the glutamatergic system to the French language. Once you learn the rules, you're like, “Oh, I have it,” and then you realize there are quite a few exceptions. Where the receptor is located is very important in the glutamatergic system. It's very complicated and so is depression, so it's appropriate that we're looking at glutamate as a target in major depressive disorder.

Chepke: What’s interesting is that there is some convergence with the monoamine system. The monoamines are all found in the brainstem or the midbrain and they project up through the cortex and they project it onto a lot of glutamatergic neurons. 

One theory as to why it takes so long for antidepressants that are based on the monoamines to work is because it has to go through those intermediaries to get to the glutamate system and then eventually can have downstream effects on neuroplasticity, whereas if you have a direct glutamatergic antidepressant, you cut out that middle-man—you go straight to the glutamate get the neuroplasticity and that's why we may see the rapid effects we see with the glutamatergic antidepressants. 

Dambrino: Absolutely.

PCN: What are the most significant clinical findings regarding glutamatergic antidepressants, and how do these findings translate into better symptom resolution for patients with treatment-resistant depression? 

Dambrino: The first glutamatergic agents for major depressive disorder were FDA approved between 2019 and 2022. The first oral antidepressant, which also has monoaminergic activity, was bupropion and dextromethorphan. 

The primary way that that medication works on the glutamatergic system is that bupropion is a cytochrome P450-2D6 inhibitor. It increases and prolongs the plasma concentration of dextromethorphan, which is really interesting. In randomized double-blind placebo-controlled phase 3 trial, as early as week 1, the symptom reduction in depression was statistically significant, which is really exciting because we know that the earlier that we treat depression effectively, the better the outcomes. Dr Chepke is going to talk about the efficacy of ketamine as well in clinical trials. 

Chepke: But first, just to underline that that rapid onset, I think, that's the most important clinical finding possibly with the glutamatergic antidepressants because if nothing else, it brings hope to the patients. When someone's struggling with a major depressive disorder by virtue of the disease itself, it robs them of hope and so to let tell them that, “Hey, you're going to take this medication and best-case scenario you'll feel nothing for 4 to 5 weeks (because if you feel something before that it'll probably be side effects) and you won't feel any positive results probably for at least a month,” that's not what they need. That's not what they want to hear and that can rob them of hope, so to get benefit early on can really help with that illness specifically. 

That’s been a common theme with the glutamatergic antidepressants. You mentioned esketamine, approved in 2019 initially for treatment-resistant depression, later in major depression with suicidal ideation. That was the big thing that was found in the early 2000s with ketamine, the original trials, that there was a rapid onset within just hours and that was sustained for some period of time, it did need some periodic treatments, but that we can see rapid-acting benefits and that they can be durable as well. This is something that is completely new for us and completely new for patients. It just fills a huge unmet need and I think can really bring a lot of benefits to people who either have treatment-resistant depression and have just been failed by the monoaminergic antidepressants and patients, because as I always say, patients don't fail medications, medications fail patients, don't blame the victim. But anyone with MDD could benefit from this because who wouldn't want to have a faster onset of a medication? 

Dambrino: Absolutely, I can't tell you how many times I've heard patients say, “When am I going to feel better?” They've been suffering for a long time, so the sooner that they can feel better the better, and so it's nice that we have this data that supports that that can happen earlier than we thought.

Thank you so much for joining us. I'm Kristian Dambrino.

Chepke: And I'm Craig Chepke. Please check back with Psych Congress Network for more content, as we update on a regular basis, both on this topic as well as everything in psychiatry.

Craig Chepke, MD, DFAPA, is a board-certified psychiatrist in clinical practice as the medical director of Excel Psychiatric Associates in Huntersville, NC, and is an Adjunct Associate Professor of Psychiatry for the Sandra and Leon Levine Psychiatry Residency Program at Atrium Health. Dr Chepke is the scientific director for the Psych Congress portfolio of CME conferences, and he has been recognized as a Distinguished Fellow of the American Psychiatric Association.

Kristian Dambrino, DNP, PMHNP-BC, is a board-certified psychiatric mental health nurse practitioner and the founder of Dambrino Wellness, an outpatient mental health practice in Nashville, TN. She received her Doctor of Nursing Practice from Belmont University College of Nursing, with a focus on innovative global nursing partnerships in Indonesia. Having worked extensively with severe and persistent mental illness in community mental health and crisis settings, Dambrino embraces a trauma-informed, evidence-based prescribing model for her patients.

© 2025 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Psych Congress Network or HMP Global, their employees, and affiliates.